1. Field of the Invention
The present invention is directed to novel compounds which have retinoid like biological activity. More specifically, the present invention relates to diene compounds substituted with a phenyl or heteroaromatic moiety where the ring connection is adjacent to a substituent group in the heterocycle, the diene being further substituted with a tetrahydronaphthyl or analogous group. The present invention also relates to pharmaceutical compositions comprising these compounds as the active ingredient and to methods of using the compounds and compositions.
2. Brief Description of the Background Art
The biological activity of retinoic acid is known and has been the subject of numerous literature references.
A relatively large number of retinoic acid analogs (retinoid like compounds) have been synthesized in the prior art, and are described in numerous patents and scientific publications. For example, U.S. Pat. No. 4,326,055 discloses ethene derivatives which have a substituted phenyl ring and a substituted indane or tetrahydronaphthalene group. The compounds are described as tumor inhibiting agents, and useful for treating dermatological conditions and rheumatic illnesses.
U.S. Pat. No. 4,723,028 discloses diphenylethene (stilbene) derivatives which have retinoic acid-like activity.
U.S. Pat. No. 4,740,519 discloses certain aromatic heterocycle derivatives which have retinoic acid-like activity.
Published European Patent Application 0130795 discloses ethene derivatives, where the ethene moiety is substituted by a substituted phenyl group and by a substituted chroman, thiochroman or quinoline group. The compounds are useful for inhibiting the degradation of cartilage in mammals.
European Patent Application 176034A (Published Apr. 2, 1986) discloses tetrahydronaphthalene compounds having an ethynylbenzoic group. U.S. Pat. No. 4,739,098 discloses compounds wherein three olefinic units from the acid-containing moiety of retinoic acid are replaced by an ethynylphenyl functionality. These compounds have retinoic acid-like biological activity.
Published German Patent Application DE 3529032 A1 discloses di-phenyl substituted butadiene compounds having retinoid-like activity.
U.S. Pat. No. 4,810,804 (issued on Mar. 7, 1989) based on an application of the same inventor and assigned to the same assignee as the present application, discloses such disubstituted acetylene compounds wherein one of the substituents of the acetylene group is a substituted phenyl group, and the second substitutent is a substituted or unsubstituted 6-chromanyl, 6-thiochromanyl or 6-tetrahydroquinolinyl group. The compounds disclosed and claimed in U.S. Pat. No. 4,810,804 have retinoic acid-like biological activity.
The publication Cancer Research 44, 190-195, January 1984 Dawson et. al. discusses the relationship between binding affinities to cellular retinoic acid binding protein and the biological potency of a new series of retinoids. The synthesis of the latter compounds is disclosed in Dawson, Journal of Medicinal Chemistry, 1981, Vol. 24, No.5 591.
A publication titled "Aromatic Retinoic Acid Analogues Synthesis and Pharmacological Activity" by M. I. Dawson et al. Journal of Medicinal Chemistry 1981 Vo. 24 p 583-592 discusses structure activity relationships of certain synthetic retinoids and describes the synthesis of certain phenyl and cyclohexenyl substituted butadienes and hexatrienes as retinoid analogs.
A publication by L. W. Spruce et al. titled Novel Heteroarotinoids: Synthesis and Biological Activity Journal of Medicinal Chemistry 1991 Vol. 34, p. 430 describes certain thiochromanyl and cyclopropyl substituted butadienes as retinoid analogs.
The synthesis of 2-furancarboxylic acid, 5-(methylthio)-3-(4-phenyl-1,3-butadienyl)-,ethyl ester is disclosed in Tetrahedron, 45(23), 7631-40 (Eng) 1989.
Several co-pending applications and recently issued patents of the present inventor, which are assigned to the assignee of the present application, are directed to further compounds having retinoic acid-like acitivity.